The primary content for the gamma-secretase complex is maintained at the dedicated protein page:
This page provides a comprehensive overview of:
- Subunit composition: presenilin-1/2 (catalytic), nicastrin, APH-1, PEN-2
- Structural biology: cryo-EM architecture (PDB: 5A63, 6IDF, 5FN2), active site geometry, conformational flexibility
- Catalytic mechanism: processive cleavage of Aβ49→Aβ46→Aβ43→Aβ40 and Aβ48→Aβ45→Aβ42→Aβ38
- Substrates: Notch receptors, APP, ErbB4, E-cadherin, CD44, LRP1, EphB2
- Role in Alzheimer's disease: FAD mutations in PSEN1/PSEN2 alter Aβ42/Aβ40 ratio, 300+ pathogenic mutations known
- Therapeutic targeting: GSI failures (semagacestat, avagacestat, tarenflurbil), GSM development, gene therapy approaches
- Research tools: experimental systems, animal models, patient-derived iPSC neurons
Gamma-secretase is central to AD pathogenesis as the enzyme that produces amyloid-beta peptides. The protein page at /proteins/gamma-secretase contains over 60 references and is continuously updated with the latest structural and clinical research.